Animals and humans suffer from endoparasitical infections including, for example, helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause severe economic losses in pigs, sheep, horses, and cattle as well as poultry. Parasites which occur in the gastrointestinal tract of animals and humans include those of the genera Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, Haemonchus, Ostergagia, Trichostrongylus, Oesophagostomum, Cooperia, Bunostomum, Strongylus, Cyathostomum and parasites which are found in the blood or other tissues and organs such as Dirofileria, Onchocerca, Dictyocaulus. 
Macrolide anthelmintic compounds may be used for treating endo- and ectoparasite infections and infestations in mammals and birds. Compounds that belong to this class include the avermectin and milbemycin series of macrolides. These compounds are potent antiparasitic agents that are effective against a wide range of internal and external parasites. Avermectins and milbemycins share the same common 16-membered macrocyclic lactone ring; however, milbemycins do not possess the disaccharide substituent on the 13-position of the lactone ring. In addition to treating parasitic insects, ticks and mites, avermectins and milbemycins are used to treat endoparasite infections in warm-blooded animals.
The avermectins may be isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The production, isolation and structural determination of the avermectins are documented in Albers-Schonberg, et. al, J. Am. Chem. Soc. 1981, 103, 4216-4221 and references cited therein. The description of the morphological characteristics of the culture is described in U.S. Pat. No. 4,310,519, which is incorporated herein by reference. The eight different naturally occurring avermectins have the following structures:
wherein A at the 22,23 position indicates a single or a double bond; R1 is hydrogen or hydroxyl; R2 is iso-propyl or sec-butyl; and R3 is hydroxy or methoxy. Conventional differentiation of the naturally occurring congeners is denoted as follows:
congener(A)R1R2R3A1adouble bond—Hsec-butyl—OCH3A1bdouble bond—Hiso-propyl—OCH3A2asingle bond—OHsec-butyl—OCH3A2bsingle bond—OHiso-propyl—OCH3B1adouble bond—Hsec-butyl—OHB1bdouble bond—Hiso-propyl—OHB2asingle bond—OHsec-butyl—OHB2bsingle bond—OHiso-propyl—OH
Isolation of the avermectins generally provides a mixture of the “a” and “b” components in a ratio of 4:1, respectively. Separation of the “a” and “b” components can be achieved via standard chromatographic techniques, however this is seldom done in practice as the minimal differences in the R2 substituents of these derivatives confer little effect on chemical reactivity or biological activity of the compounds. Thus, the presence of the mixture is indicated by referring to the congeners as A1, A2, B1, or B2 while omitting the “a” and “b” designation.
The milbemycins are the aglycone derivatives of the avermectins, such as those described, for example in U.S. Pat. Nos. 4,144,352; 4,791,134; and 6,653,342, which are incorporated herein by reference. Particularly important anthelmintics of this family include moxidectin, as described, for example in U.S. Pat. Nos. 7,348,417; and 4,916,154 (and references cited therein, all incorporated herein by reference).
The avermectin and milbemycin series of compounds either are natural products or are semi-synthetic derivatives. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519, and the 22,23-dihydro avermectin compounds are disclosed in U.S. Pat. No. 4,199,569, all of which are incorporated herein by reference. The synthesis of avermectins has been documented (J. Am. Chem. Soc. 1989, 111, 2967; J. Am. Chem. Soc. 1986, 108, 2776) and research on deconjugation and epimerization of avermectin derivatives is also described in Hanessian, et al (J. Am. Chem. Soc. 1987, 109, 7063) and Fraser-Reid, et al (J. Am. Chem. Soc. 1987, 109, 933). For a general discussion of avermectins, which includes a discussion of their uses in humans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, ed., Springer-Verlag, New York (1989). Naturally occurring milbemycins are described in Aoki et al., U.S. Pat. No. 3,950,360 as well as in the various references cited in “The Merck Index” 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996).
Examples of avermectins include abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Examples of milbemycins include milbemectin, milbemycin D, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins, respectively.
The macrocyclic lactone compounds are known in the art and can easily be obtained commercially or through synthesis techniques known in the art. Reference is made to the widely available technical and commercial literature. For avermectins, such as ivermectin and abamectin, reference may be made, for example, to the work “Ivermectin and Abamectin”, 1989, by M. H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., or Albers-Schönberg et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin, “Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may be consulted. For milbemycins, reference may be made, inter alia, to Davies H. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973 and EP 0 677 054.
The avermectins and milbemycins demonstrate potent antiparasitic activity while being relatively non-toxic to most mammalian species. As a result, the avermectin/milbemycin family has been the focus of extensive chemical modification studies, which are outlined, for example, in U.S. Pat. Nos. 4,199,569; 4,310,519; 4,423,209; 4,427,663; 4,457,920, 4,806,527; 4,831,016; 4,855,317; 4,859,657; 4,871,719; 4,873,224; 4,874,749; 4,895,837; 4,906,619, 4,920,148; 4,963,582; 4,973,711; 4,978,677; 5,015,630, 5,023,241, 5,030,622; 5,055,454; 5,055,596; 5,057,499; 5,077,308; 5,162,363; 5,169,839; 5,208,222; 5,244,879; 5,262,400; 5,830,875; and 7,250,402. Chemical modifications have also been induced via spiking the fermentation broth with acids, which are subsequently incorporated at the C-25 position of the avermectins (EP 0 214 731, and Arch. Biochem. Biophys 1989, 269, 544-547). All of these documents and references cited therein, as well as the references cited herein, are expressly incorporated by reference.
Notwithstanding the excellent progress in antiparasitic research, concerns remain with respect to increasingly common reports of resistance among veterinary parasites (Parasitology 2005, 131, S179-190). Thus, there remains an ongoing need for novel endectocides and anthelmintic treatments in veterinary medicine. It is an object of this invention to provide novel endectocides and anthelmintic compounds and formulations, as well as methods of treatment using such compounds. That the invention performs as herein described is surprising, unexpected and non obvious.
All documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.
Citation or identification of any document in this application does not constitute an admission that such document is available a prior art to the present invention.